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Role of intercellular communication in pathogenesis of diabetic retinopathy

细胞间通讯在糖尿病视网膜病变发病机制中的作用

基本信息

批准号：
10225557
负责人：
Sayon Roy
金额：
$ 43.17万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2022-04-20
项目状态：
已结题

项目摘要

Project Summary The overall goal of this research is to establish whether maintenance of connexin 43 (Cx43)-mediated gap junction intercellular communication (GJIC) and Cx43 hemichannel (HC) activity in the retinal capillaries of diabetic patients plays a protective role against the development of retinal vascular cell loss and vascular permeability associated with diabetic retinopathy (DR). Substantial evidence suggests that reduced GJIC activity in retinal vascular cells may contribute to the breakdown of homeostatic balance in DR (1-4). We have shown that the expression of Cx43, the principal gap junction protein, is downregulated in retinal vascular cells in high glucose (HG) condition with concomitant reduction in GJIC activity (3, 4) that contributes to loss of retinal vascular cells and capillary leakage. Preliminary data indicate HG reduces Cx43 HC activity and trigger apoptotic cell death (5). Recently, we observed that maintenance of cell-cell coupling inhibits HG-induced apoptosis and excess cell monolayer permeability in vitro (6). Based on these findings, we hypothesize that preventing hyperglycemia-induced Cx43 downregulation and GJIC activity would promote vascular homeostasis, restore Cx43 HC activity and Cx43 phosphorylation, ultimately preventing loss of retinal vascular cells and capillary leakage in DR. The hypothesis is supported by findings from previous funding period that showed (i) HG-induced downregulation of Cx43 expression contributes to the breakdown of endothelial barrier tight junctions by reducing ZO-1 and occludin expression (7, 8) and that restoration of Cx43 expression (7) and gap junction coupling prevents HG-induced apoptosis and cell monolayer permeability in retinal endothelial cells (6); (ii) Cx43 expression is downregulated in human retinas, and that the severity of retinal vascular cell loss is linked to the extent to which Cx43 downregulation develops (9). The hypothesis is also supported by key preliminary data that Cx43 phosphorylation is altered at s368 and s373 negatively impacting Cx43 functionality in GJIC and HC activity. Additionally, reports indicate that ZO-1, a component of the tight junction, interacts directly with Cx43 (10), and regulates Cx43-mediated GJIC activity (11, 12). Having observed ZO-1 to be reduced in retinal vascular cells by HG/diabetes (13), we propose to examine whether Cx43 downregulation, compromised GJIC, altered HC activity, and altered Cx43 phosphorylation promotes retinal vascular cell loss and tight junction dysfunction in vascular permeability. Findings are expected to provide valuable insight into a novel mechanism underlying retinal vascular cell loss and capillary leakage, and a potential strategy to prevent retinal vascular lesions in DR.

项目概要本研究的总体目标是确定连接蛋白 43 (Cx43) 介导的间隙是否维持视网膜中的细胞间连接通讯 (GJIC) 和 Cx43 半通道 (HC) 活性糖尿病患者的毛细血管对视网膜血管细胞损失的发展具有保护作用以及与糖尿病视网膜病变（DR）相关的血管通透性。大量证据表明视网膜血管细胞中 GJIC 活性的降低可能导致 DR 体内平衡的破坏（1-4）。我们已经证明，主要间隙连接蛋白 Cx43 的表达是在高葡萄糖（HG）条件下视网膜血管细胞下调，同时伴随着 GJIC 活性 (3, 4) 导致视网膜血管细胞损失和毛细血管渗漏。初步数据表明 HG 会降低 Cx43 HC 活性并引发细胞凋亡 (5)。最近，我们观察到维持细胞间偶联可抑制 HG 诱导的细胞凋亡和细胞单层通透性过剩体外 (6)。基于这些发现，我们假设预防高血糖诱导的 Cx43 下调和 GJIC 活性将促进血管稳态、恢复 Cx43 HC 活性和 Cx43 磷酸化，最终防止 DR 中视网膜血管细胞的损失和毛细血管渗漏。该假设得到了先前资助期的研究结果的支持，该研究结果表明：(i) HG 引起的 Cx43表达的下调有助于内皮屏障紧密连接的破坏减少 ZO-1 和 occludin 表达 (7, 8) 并恢复 Cx43 表达 (7) 和间隙连接耦合可防止 HG 诱导的视网膜细胞凋亡和细胞单层通透性内皮细胞(6)； (ii) Cx43 表达在人类视网膜中下调，并且视网膜病变的严重程度血管细胞损失与 Cx43 下调的程度相关 (9)。假设也是关键初步数据支持 Cx43 磷酸化在 s368 和 s373 处发生负面改变影响 GJIC 和 HC 活动中的 Cx43 功能。此外，报告表明 ZO-1 紧密连接的组成部分，直接与 Cx43 相互作用 (10)，并调节 Cx43 介导的 GJIC 活动 (11, 12)。观察到 HG/糖尿病导致视网膜血管细胞中的 ZO-1 减少 (13)，我们建议检查 Cx43 是否下调、GJIC 受损、HC 活性改变以及 Cx43磷酸化改变促进视网膜血管细胞损失和紧密连接功能障碍血管通透性。研究结果有望为潜在的新机制提供有价值的见解视网膜血管细胞损失和毛细血管渗漏，以及预防视网膜血管病变的潜在策略博士。